Devices, methods, and systems for the treatment and/or monitoring of damaged tissue

ABSTRACT

Disclosed are methods, devices, and systems for treatment of an abnormal wound healing response. The methods, devices, and systems can be used to treat solid ulcerated tissue, such as diabetic foot ulcers (DFUs), arthritic tissue, muscle soreness, joint pain, varicose veins, obesity, and peripheral artery disease. Additionally, the methods, devices, and systems can promote the healing of xenograft, allograft, autograft, or engineered tissue following reconstruction surgery. The methods, devices, and systems include the ability to determine an optimal set of pulse parameters that are specific to wound healing. In embodiments, the methods, devices, and systems include components for guiding the user on electrode placement based on anatomical or electrical measurements, delivering a custom series of electric pulses, applying heat, and using feedback from physiologic measurements to control the device.

This application is a continuation of Ser. No. 16/267,635, filed Feb. 5,2019, entitled DEVICE, METHODS, AND SYSTEMS FOR THE TREATMENT AND/ORMONITORING OF DAMAGED TISSUE, which claims the benefit of U.S.Provisional Application Ser. No. 62/627,028, filed on Feb. 6, 2018,entitled DEVICE, METHODS, AND SYSTEM FOR THE TREATMENT OF WOUNDS, whichare incorporated by reference in their entireties herein.

FIELD OF THE INVENTION

This disclosure relates to devices, methods, and systems for thetreatment of wounds.

BACKGROUND OF THE INVENTION

Diabetic foot ulcers (DFUs) are the cause of over 80,000 amputationseach year in the United States. The number of people who lose a limb dueto diabetes is expected to triple by the year 2050. Nationally, of theover $100 billion spent annually on managing diabetes, at least 33% islinked to the treatment of DFUs.

Often, poor-healing, neuropathic wounds that occur on diabetic patients,especially on the lower extremities, will only worsen if left untreated,in part due to impairment of blood flow. Patients who have diabetesexperience reduced blood flow in the limbs, and ulcers often develop onthe bottom of the foot.

There is, therefore, a need for treatment and/or monitoring of DFUs in acost-effective manner that can prevent amputation.

SUMMARY OF THE INVENTION

Embodiments of the disclosure comprise devices, methods, and systems forthe treatment and/or monitoring of damaged tissue, such as wounds. Thedevices, methods, and systems may be embodied in a variety of ways, andmay provide the ability for electrical stimulation and heat treatment inat-home setting.

Accordingly, a therapeutic device is disclosed for treating damagedtissue. The device may include a heating component, which is configuredto apply heat to a limb, and a plurality of electrodes, with at leastone electrode configured to supply electrical stimulation, also to thelimb.

In one aspect, the device may further include a plurality of sensors.Optionally, at least one sensor is configured to measure at least oneindicator of wound healing.

In other embodiments, the device may also comprise a pulse generatorbeing electrically coupled with the plurality of electrodes, wherein thepulse generator is configured to generate a plurality of electricalimpulses for delivering electrical stimulation treatment to subjectthrough at least one electrode.

The device may also comprise at least one control unit to operate theelectrical pulse stimulation and the heating component. The device may,in certain embodiments, further comprise a processor, wherein theprocessor comprises processing logic and telemetry to determine atreatment regimen for increasing blood flow based on carry-over effects.

In another embodiment, the device may include one or more sensors tosense one or more physiological conditions of a person undergoingtreatment. For example, the sensors may sense at least one indicator ofwound healing.

Optionally, the method may include generating electrical pulses andapplying the electrical pulses to the limb to generate electricalstimulation.

In other aspects, the method includes processing logic and telemetry todetermine a treatment regimen for increasing, optionally maximizing, awearer's blood flow based on carry-over effects.

In yet other aspects, the method includes collecting, and optionallyrecording, stimulation data and indicators of wound healing duringtreatment and after treatment. In any of the above, suitable indicatorsmay include physiologic, such as bioimpedance, pH, heat in the wound andlower extremity, periwound status measurements.

The method may further include enabling, disabling, and/or altering theelectrical stimulation and/or heat based on the indicators. The methodmay additionally include determining future treatment parameters basedon the indicators.

In yet another aspect, a system is disclosed that includes a processingdevice; and a non-transitory computer-readable medium communicativelycoupled to the processing device, wherein the processing device isconfigured to perform operations comprising: receiving a data setassociated with patient indicators of wound healing and stimulationdata; storing the data set; generating treatment parameters based on thestored data set by determining a relationship between initial treatmentparameters and plurality of the indicators of wound healing and thestimulation data; and electronically converting the stored data set intothe next parameters based on the relationship. In certain embodiments,the system may further include a component for generating an interfacefor display that includes at least some of the data of the data set,which is associated with the indicators of wound healing and thestimulation data.

In another aspect, a method of treating damaged tissue is disclosed. Themethod may comprise the steps of applying heat and electrical simulationto or adjacent the damaged tissue.

In one aspect, the method includes applying heat and electricalsimulation to at least a portion of the limb with the damaged tissue.Further, applying the heat includes applying the heat to at least 40%,or at least 50%, or at least 60%, or at least 70%, or at least 80%, orat least 90%, or about 100% of the portion of the limb to effect globalwarming of the limb.

In a further aspect, the method applying heat and electrical simulationto the limb with the damaged tissue. Further, applying the heat includesapplying the heat to at least 40%, or at least 50%, or at least 60%, orat least 70%, or at least 80%, or at least 90%, or about 100% of thelimb to effect global warming of the limb.

In one embodiment, the method applying heat and electrical simulation tothe limb includes applying the heat to at least 40% of the limb.

In another aspect, the method includes identifying tissue to be treated;and placing a therapeutic device with a heating component and aplurality of electrodes on the limb, wherein the device surrounds and/orcovers a significant portion of the limb; and applying heat to the limband while simultaneously conducting an electrical current through theplurality of electrodes to apply electrical stimulation to the limb.

The method may further include selecting a treatment protocol.

In some embodiments, the method may include covering at least 90%, or atleast 80%, or at least 70%, or at least 60%, or at least 50%, or atleast 40%, or at least 20% of the limb.

In some embodiments, the method further includes sensing one or morephysiological conditions of a person undergoing treatment. For example,the sensing may include sensing at least one indicator of wound healing.Additionally, the method may further include measuring the physiologicalcondition, such as the indicator of wound healing.

Optionally, the method may include generating electrical pulses andapplying the electrical pulses to the limb to generate electrical pulse.

In other aspects, the method includes processing logic and telemetry todetermine a treatment regimen for increasing, optionally maximizing,wearers blood flow based on carry-over effects.

In yet other aspects, the method includes collecting, and optionallyrecording, stimulation data and indicators of wound healing duringtreatment and after treatment.

In any of the above, suitable indicators may include physiological andbioimpedance measurements.

The method may further include enabling, disabling, and/or altering theelectrical stimulation and/or heat based on the indicators. The methodmay additionally include determining future treatment parameters basedon the indicators.

In yet another aspect, a system is disclosed that includes a processingdevice; and a non-transitory computer-readable medium communicativelycoupled to the processing device, wherein the processing device isconfigured to perform operations comprising: receiving a data setassociated with patient indicators of wound healing and stimulationdata; storing the data set; generating treatment parameters based on thestored data set by determining a relationship between initial treatmentparameters and plurality of the indicators of wound healing and thestimulation data; and electronically converting the stored data set intothe next parameters based on the relationship. In certain embodiments,the system may further include a component for generating an interfacefor display that includes at least some of the data of the data set,which is associated with the indicators of wound healing and thestimulation data.

Before the various embodiments disclosed herein are explained in detail,it is to be understood that the claims are not to be limited to thedetails of operation or to the details of construction and thearrangement of the components set forth in the following description orillustrated in the drawings. The embodiments described herein arecapable of being practiced or being carried out in alternative ways notexpressly disclosed herein. Also, it is to be understood that thephraseology and terminology used herein are for the purpose ofdescription and should not be regarded as limiting. The use of“including” and “comprising” and variations thereof is meant toencompass the items listed thereafter and equivalents thereof as well asadditional items and equivalents thereof. Further, enumeration may beused in the description of various embodiments. Unless otherwiseexpressly stated, the use of enumeration should not be construed aslimiting the claims to any specific order or number of components. Norshould the use of enumeration be construed as excluding from the scopeof the claims any additional steps or components that might be combinedwith or into the enumerated steps or components.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic diagram illustrating one embodiment of a devicefor healing and/or monitoring damaged tissue;

FIG. 1A is cross-section taken along line IA-IA of FIG. 1;

FIG. 1B is a schematic drawing of an electrode with a sensor integratedor co-located with the electrode;

FIG. 1C is a schematic diagram illustrating another embodiment of thedevice for wound healing in accordance, which is capable of guidingelectrode placement around a wound or a distal nerve, applyingelectrical stimulation, applying heat, and/or monitoring blood flow tocontrol the treatment endpoint;

FIG. 2 is a schematic cross-section of the device of FIG. 1A;

FIG. 2A is a side by side image of a thermal map (left (39.7° Catcrosshair)) of a prototype and an image of the prototype (right);

FIG. 3 shows a data display of a healthy human subject with 15 mA ofelectric stimulation in accordance with an embodiment of the disclosure(blood flow (top), skin temp (middle), and stimulation waveform(bottom));

FIG. 4 shows supporting data from human subjects wearing the device inaccordance with an embodiment of the methods (blood flow (bloodperfusion units (BPU), black) doubles as temperature (° C., gray)increases);

FIG. 5 shows a block diagram illustrating a control unit in accordancewith an embodiment of the disclosure;

FIG. 6 shows a flow chart illustrating the decision tree based onphysiologic measurement feedback in accordance with an embodiment of thedisclosure; and

FIG. 7 shows an experimental setup used to acquire supporting data inaccordance with an embodiment of the disclosure.

DETAILED DESCRIPTION

As will be more fully described below, disclosed herein are devices,methods, and systems for treating and/or monitoring damaged tissue,including treating and/or monitoring ulcers, such as diabetic ulcers.The disclosed devices, methods, and systems may reduce the risk of woundinfection, treat infection, and/or promote healing of damaged tissue,such as wounds, via the joint application of heat and electricalstimulation. The devices, methods, and systems may be embodied in avariety of ways. Further, although described in reference to a human orperson, it should be understood that the devices, methods, and systemsdisclosed herein may also be used on animals.

Referring to FIG. 1, the numeral 10 generally designates a device fortreating and/or monitoring damaged tissue, such as a wound. Device 10includes at least two or more electrodes 11 for attaching to a person'slimb at or near the damaged skin to apply electrical stimulation to theunderlying tissue, including muscles, nerves, and optionally tendons.For example, electrodes 11 may include self-adhesive electrodes,including self-adhesive rubber electrodes, or taped-on electrodes.Optionally, the electrodes may comprises dry fabric electrodes fromconductive thread or carbon electrodes for MRI compatibility.

Alternately, the electrodes 11 may be applied to a location remote fromthe damaged skin, for example, over a muscle or nerve that extends intothe limb. See below discussion of additional embodiments for furtherdiscussions of suitable locations for the electrodes.

Device 10 also includes a control unit 12, which is powered by a batteryor other source of current/voltage (such as a standard 120-volts walloutlet) and is in electrical communication with electrodes 11 viaelectrical leads 11 a, 11 b (FIG. 1) and configured to supply electricalcurrent to at least one of the electrodes. Accordingly, depending on thetype of current (AC/DC) and/or voltage provided or delivered to controlunit 12, control unit 12 may include a converter (AC to DC or DC to AC)and a transformer to adjust (such as reduce or increase whereapplicable) the supplied voltage and one or more resistors to adjust(e.g. reduce) the current to suitable levels, described more fullybelow.

Optionally, control unit 12 includes a controller and a pulse generator,which is electrically coupled to the controller and to the source ofelectricity (either directly or through the controller via electricalleads), which can generate a plurality of electrical impulses fordelivering an electrical pulse wave form to the at least one electrodefor applying to the person's skin or tissue, to thereby administer theelectrical pulse stimulation treatment through electrodes 11. Dependingon where and how much current is applied, and where the electrodes areplaced, the electrical stimulation may induce neuromuscular stimulation(NMES) or transcutaneous stimulation (TENS) or microtens (MCT)stimulation. Optionally, the pulse generator generates a biphasic pulsewave form, for example, a symmetric biphasic wave form. Again, forfurther discussion of suitable wave forms, reference is made to thedescription that follows.

Control unit 12 may be constructed of an electrical component, or groupof electrical components, which are capable of carrying out thefunctions described herein. As noted, control unit 12 may include acontroller, such as a conventional microcontroller or group ofconventional microcontrollers. In general, the controller includes anyone or more microprocessors, field programmable gate arrays, systems ona chip, volatile or nonvolatile memory, discrete circuitry, and/or otherhardware, software, or firmware that is capable of carrying out thefunctions described herein, as would be known to one of ordinary skillin the art. Such components can be physically configured in any suitablemanner, such as by mounting them to one or more circuit boards, orarranging them in other manners, whether combined into a single unit ordistributed across multiple units. When implemented to communicate witha remote device, including a server, a phone, a pad, or other hand heldelectronic device, the control unit 12 may include a communicationdevice, such as a Bluetooth device, a WiFi device, or a micro USB, whichcan provide a communication interface with the remote device.

Where device 10 is configured for use in a home setting, the pulsegenerator may generate a biphasic pulse wave form with an amplitude in arange of 1-50 mA (milliamperes), or 10-40 mA, or 15-35 mA, andoptionally about 20 mA depending on the desired stimulation. The pulsewidth may be in a range of 10-1000 ps (micro seconds), 50-800 ps,300-500 ps, again depending on the desired stimulation. For example, forsmaller muscles, a suitable amplitude may be around 30 mA and a pulsewidth may fall in a range of 50-200 ps. For example, for larger muscles,a suitable amplitude may be around 50 mA and a suitable pulse width mayfall in a range of 300-500 ps. For nerves, a suitable amplitude may bearound 20 mA and a suitable pulse width may fall in a range of 20-100μs. It should be understood that these are exemplary only, and that theamplitude in milliamps and pulse width varies not only on the type oftissue but the habitus of the tissue being stimulated. The principlesfall under the concept of the strength-duration curve. As a result, theamplitude of the current can vary based on the person and/or type oftissue to be stimulated and/or the type of tissue damage that is beingtreated and/or location of treatment. Further, as noted, the electricalcurrent may be an AC current or DC current, and in some settings a highvolt direct current (HVDC).

When configured for use in a medically supervised setting, these valuesmay be adjusted. For example, in medically supervised setting, the pulsegenerator may generate a biphasic pulse wave form with an amplitude in arange of 0.25 mA to 100 mA, 10 mA to 75 mA, or optionally about 20 mAdepending on the desired stimulation. The pulse width may be in a rangeof 50 to 500 μs, 100 to 300 μs, or optionally about 250 μs, againdepending on the desired stimulation. For example, for smaller muscles,a suitable amplitude may be around 20 mA and a pulse width may be around250 μs. For larger muscles, a suitable amplitude may be around 30 mA anda suitable pulse width may be about 300 μs. For nerves, a suitableamplitude may be around 20 mA and a suitable pulse width may fall in arange of 20-100 μs.

Optionally, in addition to electrical stimulation, electrodes 11 may beused to warm the tissue and, therefore, form a heating component. Inorder to achieve a warming effect, the pulse generator may generates apulsed radio-frequency range in the range of 50-500 kHz, with anamplitude in the range of 1 to 100 V or 50 to 100V, and a duty cycle 1%to 100% (pulsed-to-continuous on-time). This could help to heat deepinto the limb, especially if you place the electrodes on opposite sides.Further, the pulse generator may be adjustable and configured (e.g. bycontrol unit 12) to switch between an electrical stimulation modalityand a warming modality where different wave forms are desired for eachdesired effect.

Optionally, in lieu of or in addition to warming using electrodes 11,device 10 may include a separate heating component 14, which may becontrolled by control unit 12. Heating component 14 may be in the formof an electric heating coil, an electronic heater, such as a Peltierdevice or infrared LEDS, or heated fluid (such as water that flowsthough channels or tubing), or chemical warmers that when bent orpressed start a chemical exothermic reaction. The heating component 14is further configured so that it “globally” heats the limb (or portionof the limb) that includes the damaged tissue. The term “global” or“globally” refers to raising the temperature of the limb (or portion ofthe limb) and not just local warming of the limb where the limb surfaceand the tissue beneath the surface are warmed. To achieve globalwarming, heat is applied about 40%-100% of the limb or body part (orportion of the limb or body part), and optionally to at least at least40%, or at least 50%, or at least 60%, or at least 80%, or at least 90%,or about 100%.

In one embodiment, globally warming the limb is achieved by wrapping theheating component 14 around the limb (or portion of the limb) so that itcovers at least 20%, or at least 30%, or at least 40%, or at least 50%,or at least 60%, or at least 70%, or at least 80%, or at least 90%, orabout 100% of the limb or body part (or portion of the limb or bodypart). To that end, heating component 14 may be mounted (includingencasing it) in a covering 16 that is suitable for wrapping around thelimb being treated. The covering may be in the form of a large patch ofmaterial or materials, including fabric, which may be assembled frommultiples layers (e.g. 16 a, 16 b, and 16 c), with the separate heatingcomponent sandwiched between two of the layers, and the layer 16 atouching the person's skin being formed from a material that iscomfortable to the touch. Optionally, two or more layers may be joinedtogether to form a bladder for inflating the covering or for forming aconduit(s) through which warming fluid may be circulated to form theheating component.

Additionally, as described below, the patch may include a layer ofthermally conductive material, for example, to transfer the heat to agreater area than the footprint of the heating component and/or a layerof thermally reflective material, either or both of which may increasethe efficiency of the heat transfer from the heating component to thelimb or body part. Optionally, electrodes 11 may be integrated into orsimply be co-located with the covering 16 (e.g. placed under covering 16on skin, but not necessarily attached to the covering).

To provide an efficient transfer of heat from the heating component 14to the person's skin, heating component 14 is located adjacent layer 16a, which is placed on the person's skin. Optionally, as noted, toincrease the efficiency, one or more of the layers (e.g. layer 16 b) mayform a thermally conductive and/or reflective layer to form aninsulation layer, and may be formed from a heat reflective material,such as heat reflective thin plastic (such as a foil or a thin plasticsheet coated with a metallic reflecting agent, such as metallizedpolyethylene (MPET)). To protect the various layers and/or providecushioning, layer 16 c may comprise a protective outer layer, such as afoam, including neoprene. Alternately or in addition, as noted above anddescribed below, one of the layers may be a thermally conductive layerto transfer the heat from the heating component across the limb—eitherto provide a more uniform distribution of the heat and/or to facilitatetransfer of the heat beyond the immediate “footprint” of the heatingcomponent.

Additionally, the patch of fabric may be shaped to conform to theperson's limb. For example, as described in reference to the embodimentsdescribed below, the covering or patch may be configured into the shapeof a boot, covering the lower portion of a leg. For example, thecovering may start at the knee and extend to and optionally enclose thefoot, for example, in the case of treating ulcers on the heel of aperson. Or the patch may be configured as a sleeve to cover an armand/or shoulder, or other body part. For additional or alternate detailsof the various layers of material that can be assembled to form covering16 and to encase the heating component, reference is made to FIG. 3 andthe corresponding description.

In another embodiment, described more fully in reference to theadditional embodiments below, device 10 may include one or more sensors18 in communication (electrical or wireless) with control unit 12.Similar to electrodes 11, sensors 18 may be separately mounted from thecovering 16, co-located with covering 16, or integrated with covering16. For example, similar to electrodes 11, sensors 18 may be located atthe surface of layer 16 a, for example, by surface mounting or flushmounting them to or in layer 16 a (FIG. 1A). When separately mounted orco-located with covering 16, sensors 18 may be mounted to the skin ofthe person using an adhesive strip or an adhesive, including an adhesivewith a very low pull force required for removable, such as a conductiveadhesive gel, including HYDROGEL, which is tacky enough to hold a smalldevice, such as a sensor, in place, especially when then covered bycovering 16, but is easily removed to avoid damage to the person's skin.

Further, the sensor or sensors 18 may be co-located with and/orintegrated with the electrode. For example, referring to FIG. 1B, theelectrodes 11 may have an annular or donut shape with central opening(or a non-circular shape with an opening). The sensor, such as anoptical sensor, including a blood flow sensor (e.g., IR LED+photodiode),can then be optionally co-located in the central opening of theelectrode so that, for example, the electrode may hold the sensor inplace. Further, it may be integrated into the electrode by commonlymounting the sensor with the electrode on a shared substrate on whichboth the sensor and electrode are mounted.

The sensors may be used to sense and, optionally, measure one or morephysiological conditions of a person undergoing treatment and forwardsensor signals to the microprocessor of the control unit 12, containingmeasurement data, for processing. In some embodiments, the data from thesensor signals may be sent to a remote location, for example, formonitoring the wound, which is more fully described below.

For example, the sensing may include sensing at least one condition thatis an indicator of healing, such as wound healing, or the status of thedamaged tissue, such as the wound, including whether there is aninfection present. In one embodiment, sensors 18 may monitor stimulationdata and indicators of wound healing during treatment and/or aftertreatment. Such indicators may be physiological, such as bioimpedancemeasurements, blood flow, blood flow volume, pH of the wound,temperature of the wound, temperature of the limb, sensor of periwoundregion for abnormal moisture or exudate. For example, control unit 12may be configured to adjust the applied heat based on the sensorreadings from the temperature sensor(s) and optionally provide closedloop feedback control of the heating component to avoid over heating orto increase the heat when the temperature is too low.

Suitable blood flow/blood volume sensors include photoplethysmography(PPG)-blood flow sensors and pulse oximeter sensors, which use twofrequencies of light (red and infrared) to determine the percentage (%)of hemoglobin in the blood that is saturated with oxygen. The percentageis called blood oxygen saturation, or SpO2, which can be used to computeblood volume.

Suitable infections sensors include sensors to detect pH, including theuse of in wound-pH strips, which change color in response to the pHlevels; electro-chemical bio sensors; temperature sensors to detectwound temperature, including the use of in-wound temperature strips; orsensors that detect myeloperoxidase, including myeloperoxidaseresponsive materials; which change color in response to elevatedmyeloperoxidase levels. In any of the above noted visual indicators,electrical sensors (e.g., optical sensors) may then be used to detectthe visual changes in the indicators, which can then be transmitted tothe control unit 12.

Suitable sensors, as noted, include optical sensors (e.g. light sourcescombined with photodiodes to measure reflectance or absorption of thelight in the tissue, for example to measure oxygen) and Doppler probesto measure blood flow; blood flow volume (BVP) sensor orphotoplethysmography to measure blood flow volume; Hall Effect sensorsor probes to monitor the stimulation current delivered to the skin;temperature sensors, such as skin temperature probes, to measuretemperature; pH sensors; moisture sensors; or a voltage sensor, such asa differential high voltage probe, to measure the applied voltage to theskin or tissue.

To detect infection, sensors 18 may comprise: a pH sensor (e.g. measuresactivity of hydrogen ions in the tissue or blood) to measure the pH ofthe skin, with a low pH correlating to an oncoming infection; atemperature sensor to measure the temperature of the skin (as notedabove), with an increase in heat being used to indicate an infection;and/or a moisture sensor, with an increase in moisture correlating to aninfection. The sensor may detect moisture balance in and around thewound to help prevent maceration of the periwound area. A suitablemoisture sensor includes an electro-chemical bio sensor.

Accordingly, when an infection is detected or suspected, control unit 12may be configured to stop operation of device 10 and, further,optionally generate a signal either locally (e.g. an alarm signal thatgenerates a visual or audible notification) or remotely via acommunication device (described above and below) to notify a thirdparty, such as a nurse or doctor of the apparent infection.

In one embodiment, device 10 may switch between a treatment mode and amonitoring mode or device 10 may operate the modes together. Forexample, the monitoring mode may operate during pauses or temporalspaces between the pulsing of the electrical stimulation (so as not tointerfere with the measurement) or between treatment phases. In oneembodiment, control unit 12 may have a filter so that the two modes canoperate simultaneously, to filter out the signals generated by thetreatment when reading and processing the monitoring signals.

In any of the embodiments, device 10 may include a pressure sensor todetect the pressure and/or any shear applied to the wound. For example,control unit 12 may be configured to adjust treatment (e.g. reduce orstop the applied heat and/or inflation of the covering in the case of aninflatable covering) to off load pressure from the wound based on thereadings of the pressure sensor to avoid constricting the body part,such as the foot or leg.

In any of the embodiments, device 10 may include a user input device,such as a switch or a button, for example on a touch screen, to allow acaregiver (either locally or remotely) or the user to turn off thetherapy functions and allow the device to simple monitor the damagetissue, as noted above. The user input device may alternately or inaddition allow a caregiver, as noted above, to select between therapyprotocols or adjust the therapy protocols.

In another embodiment of device, device 10 may be configured as amonitoring device only, thereby eliminating the need for a heatingcomponent and/or electrodes.

Control unit 12 then may be configured to control the pulse generator(or current delivered to the pulse generator) to control the delivery ofelectrical stimulation provided by electrodes based on the sensorsignals. As noted above, it may be configured to stop the treatment ormay adjust the treatment based on input from a caregiver and/or basedthe sensor readings. To that end, the controller of control unit 12optionally includes processing logic to determine a treatment regimenfor increasing, optionally optimizing, such as by maximizing, thewearer's blood flow. For example, control unit 12 may stop or adjust oneor more characteristics of the electrical stimulation, such as the waveform, including amplitude, duration, and pulse width based on input(sensor signals or user input). In this manner, control unit 12 canprovide a closed loop feedback control of the treatment and/ormonitoring of device 10.

In yet other aspects, control unit 12 may collect, and optionallyrecord, stimulation data and indicators of wound healing duringtreatment and after treatment, which can be available for upload ordownload from control unit or, as noted above, transmitted to a remotelocation.

In another embodiment, control unit 12 may simply have a preset mode orprogram for operating the electrodes 11 and/or heating element 14. Forexample, control unit 12 may simply turn on the treatment device (basedon input from a caregiver or user) and power the electrodes 11 and/orheating component for a preselected time period with a preselectedelectrical stimulation wave form and/or temperature, and hence include atimer. Alternately, control unit 12 may be configured with presettreatment protocol programs (e.g. stored in the memory of the controlunit), which can then be either selected, using a user interface (suchas buttons or a touch screen as noted) or using a remote device.

In one aspect, a therapeutic device is disclosed for treating damagedtissue comprising a heating component; wherein heat can be applied to alimb. In another embodiment, the therapeutic device includes a pluralityof electrodes, wherein at least one electrode supplies electrical pulsestimulation. The therapeutic device, in some embodiments, furtherincludes a plurality of sensors, wherein at least one sensor isconfigured to measure indicators of wound healing. In anotherembodiment, a pulse generator is electrically coupled with the pluralityof electrodes, wherein the pulse generator is configured to generate aplurality of electrical impulses for delivering electrical stimulationtreatment to a subject through at least one electrode. The therapeuticdevice for treating damaged tissue in some embodiments, includes atleast one control unit to operate the electrical pulse stimulation andthe heating component. In other embodiments, the therapeutic deviceincludes a processor, wherein the processor includes processing logicand telemetry to determine the optimal treatment regimen for maximizingblood flow based on carry-over effects (that is when the effect of thetreatment continues after the treatment is stopped).

In a second aspect, disclosed is a method of treating damaged tissuecomprising the steps of: identifying tissue to be treated; placing atherapeutic device; selecting a treatment protocol; applying heat to alimb comprising the identified tissue; simultaneously conducting anelectrical current through the plurality of electrodes; using aplurality of sensors to record stimulation data and indicators of woundhealing during treatment and after treatment, wherein the indicators arephysiological, such as bioimpedance, pH, heat and periwoundmeasurements; enabling, disabling, and altering the electricalstimulation and heat based on the recorded indicators; and determiningfuture treatment parameters based on the recorded indicators.

In a third aspect, this invention includes a system for treating damagedtissue comprising a processing device. In one embodiment, anon-transitory computer-readable medium communicatively coupled to theprocessing device, wherein the processing device is configured toperform operations. In some embodiments, the operations of the systeminclude: receiving a data set associated with patient indicators ofwound healing and stimulation data; storing the data set; generatingtreatment parameters based on the stored data by determining arelationship between initial treatment parameters and plurality of theindicators of wound healing and the stimulation data; electronicallyconverting the stored data into the next parameters based on therelationship; and generating an interface for display that includes dataassociated with the indicators of wound healing and the stimulationdata.

Each of the embodiments of the disclosed devices, methods, and systemsallow for the rapid healing of damage tissue, such as wounds. Forexample, the disclosed devices, methods, and systems can promote healingof ulcers, such as diabetic foot ulcers (DFUs), in a shortened timeperiod with superior results.

In some embodiments, the invention can be used to treat damaged cellsincluding, but is not limited to ulcerated tissue. In addition to ulcers(such as DFUs), this device can be used to treat other damage tissue,such as arthritic tissue, tendonitis, tendon or ligament damage, musclesoreness, joint pain, varicose veins, obesity, and peripheral arterydisease.

Additionally, the device can promote the healing of xenograft,allograft, autograft, or engineered tissue following reconstructionsurgery. Wounds that can be treated by the present invention include,but are not limited to non-healing or chronic wounds. In someembodiments a wound that does not improve after at least 3, 4, or 5weeks or does not heal after at least 7, 8, or 9 weeks are non-healingwounds. Non-healing wounds include, but are not limited to DFUs,venous-related ulcerations, non-healing surgical wounds, pressureulcers, wounds related to metabolic disease, and wounds that repeatedlybreak down. Non-healing wounds place patients at an increased risk forinfections. Often, poor-healing, neuropathic wounds that occur ondiabetic patients, especially on the lower extremities, will only worsenif left untreated. Patients who have diabetes experience reduced bloodflow and nervous activity in the limbs, and ulcers often begin in highpressure areas, such as on the bottom of the foot.

Device for the Treatment of Damaged Tissue

In one embodiment, a therapeutic device for treating damaged tissueincludes: a heating component; wherein heat can be applied to a limb; aplurality of electrodes, wherein at least one electrode supplieselectrical pulse stimulation; a plurality of sensors, wherein at leastone sensor is configured to measure indicators of wound healing; a pulsegenerator being electrically coupled with the plurality of electrodes,wherein the pulse generator is configured to generate a plurality ofelectrical impulses for delivering electrical stimulation treatment to asubject through at least one electrode; at least one control unit tooperate the electrical pulse stimulation and the heating component; anda processor, wherein the processor includes processing logic andtelemetry to determine the optimal treatment regimen for maximizingblood flow based on carry-over effects.

In some embodiments, the heating component is a flexible internalheating coil. The therapeutic device, in some embodiments includes aplurality of layers comprising a heating component layer having a firstside and second side; an inner layer comprising a plurality ofdissimilar materials, wherein the inner layer contacts the subject'sskin; an outer layer comprising a plurality of dissimilar materials; anda discontinuous adhesive layer which affixes the first side of theheating layer to the inner layer and the second side of the heatingcomponent layer to the outer layer. In some embodiments, the inner layerincludes two or more sublayers.

Also in some embodiments, a first sublayer is an inner insulativesublayer, wherein the inner insulative sublayer is an absorbent polymer.In further embodiments, the insulative sublayer contacts the subject'sskin. The inner insulative sublayer, in some embodiments, includes atleast one of fleece, wool, cotton, nylon, polyester, or a combinationthereof. The inner insulative sublayer can be coated with ananti-microbial material. In further embodiments, a second sublayer is aninner conductive sublayer, wherein the inner conductive sublayer is anorganic polymer. The organic polymer may include at least one ofpolyethylene terephthalate (PET), metallized polyethylene terephthalate(MPET), or biaxially oriented PET(BoPET).

In another embodiment, the skin contacting layer may comprise athermally conductive gel, including a thermally conductive gel adhesive,such as HYRDROGEL.

The inner layer may uniformly distribute heat over the whole limb orsections thereof. In further embodiments, the thickness of the innerlayer may be from 1-50 mm, or from 2-25 mm, or from 5-10 mm.

Also in some embodiments, the outer layer includes two or moresublayers. A first outer sublayer may include a plastic mesh layer,wherein, the plastic mesh layer contacts the second side of the heatingcomponent layer. A second outer sublayer may include a synthetic rubber.In some embodiments, the synthetic rubber includes at least one ofneoprene, polyurethane, or nitrile rubber. Also in further embodiments,the thickness of the outer layer may be from 1-50 mm, or from 2-25 mm,or from 5-10 mm.

Sensors may be used to measure indicators of wound healing. Theplurality of sensors in some embodiments, include at least one ofDoppler probes, Hall Effect probes, skin temperature probes, or adifferential high voltage probe.

In some embodiments, the therapeutic device includes at least onecontrol unit to operate the electrical pulse stimulation and the heatingcomponent. Also in some embodiments, the at least one control unitincludes a thermostat for selecting an amount of energy to maintain thetissue temperature.

FIG. 10 illustrates an embodiment of a device 101 for treating damagedtissue using a thermo-regulated electrical stimulation. The therapeuticdevice may include a control unit 112 that controls a pulse generator,which can generate a plurality of electrical impulses for delivering theelectrical pulse stimulation treatment to a subject through a pluralityof electrodes 111. The device may further include a limb heating system110, which globally applies heat to a limb that contains damaged tissueto be treated. In some embodiments, the electrodes 111 are placed on askin surface in a general region of interest. The general region ofinterest may be a critical nerve and/or blood vessel. A wireless bloodflow monitor 113 can be used to record physiologic measurements.

In some aspects, the invention may include a device for applying heat tothe limb or a portion thereof. In some embodiments, heat is applied tothe whole-limb. The whole-limb may be either a leg or an arm. In otherembodiments, heat is applied to at least one section of the limb. Theleg is composed of five distinct sections: upper leg, knee, lower leg,ankle and foot. The upper leg begins at the hip and continues down tothe knee. The knee is a pivot-like hinge joint in the leg that connectthe upper and lower leg. The lower leg begins at the knee and continuesdown to the ankle. The ankle connects the lower leg to the foot. In someembodiments, heat is applied to the lower leg-ankle-foot complex. Instill other embodiments, heat is applied to at least the distalone-third of the lower limb, but is preferably applied to at least thedistal two-thirds of the lower limb. As used here, distal means furtheraway from the heart and proximal means closer to the heart. In otherembodiments, the device may be used to treat wounds on the trunk of thebody.

In some embodiments, the heating component is a flexible internalheating coil. A flexible heating component will generally allow theheating component to conform to a three-dimensional object. In someembodiments, the three-dimensional object may be a whole-limb or aportion thereof. In other embodiments, the flexible heating componentmay be a wearable garment, such as a boot, a sleeve for a shoulder, anelbow, or other body part.

In some embodiments, the heating component is internal to the device. Insome embodiments, the heating component is removable. A removableheating component can be inserted into an opening between the inner andthe outer layers. In other embodiments, the heating component will befused into a single unit. In alternate embodiments, the thickness of theheating component layer may be from 1-20 mm, or from 1-10 mm, or from1-5 mm.

In some embodiments, the heating component is run with a variablevoltage supply. In alternate embodiments, the variable voltage supplymay be from 1-120 V or from 1-24 V. A dry-cell battery can be used togenerate heat by means of an electric current. In some embodiments, thebattery will have a voltage capacity of 12 V.

In some embodiments, the device includes a plurality of layerscomprising: a heating component layer having a first side and secondside; an inner insulative layer comprising a plurality of dissimilarmaterials, wherein the inner insulative layer contacts the subject'sskin; and an outer insulative layer comprising a plurality of dissimilarmaterials; and a discontinuous adhesive layer which affixes the firstside of the heating layer to the inner layer and the second side of theheating layer to the outer layer. In some embodiments, an innerinsulative layer includes two or more sublayers. In some embodiments,the first inner insulative sublayer is an absorbent polymer, wherein thefirst inner insulative sublayer contacts the subject's skin.

The first insulative sublayer may be a woven material, a non-wovenmaterial, or a fleece. In some embodiments, the inner insulativesublayer includes at least one of fleece, wool, cotton, nylon,polyester, or a combination thereof. In some embodiments, the insulatingfabric can include a synthetic fleece. The synthetic fleece may be anonwoven fabric made from polyester. In such an embodiment, the fleecemay have a density between 50-500 g/m² or thickness may be from 1-20 mm,or from 1-10 mm or from 1-5 mm. In some embodiments, the first layer isfabricated so as to adhere poorly to wounds. In such embodiments, pooradhesion allows the device to be easily removed from the wound, enablingtreatment with limited to no pain to the patient.

In some embodiments, an inner conductive sublayer is an organic polymer.In some embodiments, the organic polymer includes at least one ofpolyethylene terephthalate (PET), metallized polyethylene terephthalate(MPET), or biaxially oriented (BoPET, i.e., MYLAR®). PET is athermoplastic polymer resin of the polyester family. PET can be spuninto fibers for permanent-press fabrics, blow-molded, or extruded. MPETis a polymer film coated with a thin layer of metal. In someembodiments, the metal is aluminum. BoPET is a polyester film made fromstretched PET. In other embodiments, an inner conductive sublayer may begraphite, copper, and silicon, and carbonaceous nanomaterials.

In some embodiments, the inner conductive sublayer is NASA foil. NASAfoil is a MPET. NASA foil is a vacuum-metallized insulating material.NASA foil is designed to be lightweight, and may be made by depositingvaporized aluminum onto thin plastic substrates. The result is a thin,flexible material that provides superior thermal-reflective properties.The flexible nature of NASA foil allows it to conform tothree-dimensional objects. In some embodiments, the three-dimensionalobject may be a whole-limb or portion thereof. In some embodiments, thethree-dimensional object may be a wearable garment (e.g., a boot). Insome embodiments, the thickness of the inner conductive layer is from1-20 mm, or from 1-10 mm, or from 1-5 mm. In aspects of the invention,the inner layer uniformly distributes heat over the whole limb. NASAfoil is ideal for equally distributing and retaining heat on treatedareas of skin due to its superior thermal-reflective properties. In someinstances, NASA foil is meant to conserve heat as a passive warmingsystem and is able to stop both evaporative and connective heat loss.

In some embodiments, the outer layer includes two or more sublayers. Insome embodiments, the first outer sublayer is a plastic mesh layer,wherein, the plastic mesh layer contacts the second side of the heatingcomponent layer. In some embodiments, the second outer sublayer is asynthetic rubber. Synthetic rubbers have elastic properties that allowthem to conform to a three-dimensional object. Such elasticity is idealas it allows the device achieve optimal contact with the area of skin tobe treated. In some embodiments, the synthetic rubber includes at leastone of neoprene, polyurethane, or nitrile rubber. In some embodiments,the thickness of the outer layer is from 1-20 mm, or from 1-10 mm, orfrom 1-5 mm.

FIG. 2 illustrates an embodiment of the invention wherein the medicaldevice includes 5 layers. The inner insulative sublayer is fleece 210with a thickness of 0.5 cm. The inner conductive sublayer is NASA foil211 with a thickness of 0.5 cm. The first outer insulative sublayer isplastic mesh 213 with a thickness of 2.0 cm. The second outer sublayeris neoprene 214 with a thickness of 1.0 cm. An internal heating coil 212is inserted in between the inner conductive sublayer 211 and the firstouter sublayer 213.

Sensors may be used to measure indicators of wound healing. In variousembodiments, the plurality of sensors include at least one of Dopplerprobes, Hall Effect probes, skin temperature probes, and a differentialhigh voltage probe. Doppler probes are capable of measuring blood flow.In some embodiments, a wide-band Hall Effect sensor is used to monitorcurrent. Skin temperature probes are capable of monitoring thetemperature of the skin at treated sites. Differential high voltageprobes can record voltage in real-time.

The therapeutic device for treating damaged tissue in some embodimentsincludes at least one control unit to operate the electrical pulsestimulation and the heating component. In some embodiments the at leastone control unit includes a thermostat for selecting an amount of energyto maintain the tissue temperature. A thermostat comprising atemperature control switch or button can be used in connection with atemperature control element of the heating component.

In further embodiments, the therapeutic device includes a processor,wherein the processor includes processing logic and telemetry todetermine the optimal treatment regimen for maximizing blood flow basedon carry-over effects.

Methods for the Treatment of Damaged Tissue

In another embodiment provided is a method of treating damaged tissue.The method may include the steps of identifying tissue to be treated;placing a therapeutic device on or around a limb encompassing the wound;selecting a treatment protocol; and applying heat and electricalstimulation to the limb and/or wound. The device may, in variousembodiments include: a heating component; wherein heat can be applied toa limb; a plurality of electrodes, wherein at least one electrodesupplies electrical pulse stimulation. The device may include aplurality of sensors, wherein at least one sensor is configured tomeasure indicators of wound healing. The device may also include a pulsegenerator being electrically coupled with the plurality of electrodes,wherein the pulse generator is configured to generate a plurality ofelectrical impulses for delivering electrical stimulation treatment to asubject through at least one electrode. The device may also include orbe in communication with at least one control unit to operate theelectrical pulse stimulation and the heating component; and a processor,wherein the processor includes processing logic and telemetry todetermine the optimal treatment regimen for maximizing blood flow basedon carry-over effects. In some embodiments, communication between atleast one control unity and the device may be wireless. For example, thestimulation circuitry may be located within the device with an externaltrigger located within a control unit, wherein the control unitcommunicates wirelessly with the stimulation circuitry within thedevice. In certain embodiments, the method may include the steps ofsimultaneously conducting an electrical current through the plurality ofelectrodes; using a plurality of sensors to record stimulation data andindicators of wound healing during treatment and after treatment,wherein the indicators are physiologic and bioimpedance measurements.The method may include enabling, disabling, and altering the electricalstimulation and heat based on the recorded indicators; and determiningfuture treatment parameters based on the recorded indicators. Asdiscussed herein for devices, the methods may be applied to a whole limbor part of a limb.

Also disclosed herein are methods for treating damaged tissue whereinthe device is placed around a limb. In some embodiments, the limb is aleg. In further embodiments, the device is placed around a leg or one ormore sections thereof. Also disclosed herein are methods wherein the atleast one control unit includes a thermostat for selecting an amount ofenergy to maintain the tissue temperature. The heating component maygenerate an amount of energy, which has been predetermined to maintainthe tissue temperature from 45-300C. or from 40-35° C.

In some embodiments of the methods, the electrodes include two or moreelectrical conductors. The electrodes may be placed on a skin surface ina general region of interest. The general region of interest may includea critical nerve or blood vessel. In other embodiments, the generalregion of interest may include the area surrounding a critical nerve orblood vessel. Critical nerves, when stimulated, may assist withvasodilation of blood vessels thus increasing blood flow. Also in someembodiments, the critical nerve may be a vasoconstrictor nerve. Infurther embodiments, the vasoconstrictor nerve may be a sciatic nerve.In other embodiments, the nerve is a tibial or peroneal nerve. In otherembodiments, the blood vessel is a femoral artery. In other embodiments,the general region of interest may be a wound. In some embodiments,electrodes may be placed to bracket the wound (e.g. placed on eitherside of wound).

Other aspects of the invention include methods for treating damagedtissue wherein a test pulse is delivered to determine the baselineelectrical impedance of the tissue and ensure proper connectivity of theelectrodes. The electrical pulses may be applied in an amount, which hasbeen predetermined to cause vasodilation of blood vessels, wherein theelectrical pulses may be applied for a pulse duration ranging from1-5000 μs, or from 2-1,000 μs, or from 5-500 μs, or from 10-50 μs. Insome embodiments, the electric pulses may have a voltage ranging from0.1-500 V, or from 5-250 V, or from 50-100 V. In some embodiments, theelectrical pulses may have a current amplitude ranging from 1-500 mA, orfrom 5-250 mA, or from 50-100 mA. In another embodiment, the electricpulses may have a voltage ranging from 0.1 to 200 V, or from 50 to100 V,or from 0.1 to 50 V. In some embodiments, the electrical pulses may havea current amplitude ranging from 1-500 mA, or from 5-250 mA, or from50-100 mA.

In other embodiments of the methods, the electrical pulses may beapplied in an amount, which has been predetermined to cause nervestimulation by using comparatively longer pulses or pulses of greaterstrength. In some embodiments, the electrical pulses may be applied fora duration ranging from 1-10000 μs, or from 2-5000 μs, or from 50-1000μs, or from 100-500 μs. In some embodiments, the electric pulses mayhave a voltage ranging from 1-1500 V, or from 50-1000 V, or from 200-500V. In another embodiment, the electric pulses may have a voltage rangingfrom 0.1-200 V, or from 0.1 to 50 V, or from 50-100 V. In someembodiments, the electrical pulses may have a current amplitude rangingfrom 1-1500 mA, or from 50-1000 mA, or from 200-500 mA.

In other embodiments, the electrical pulses may be applied in an amount,which has been predetermined to kill bacteria via non-thermalirreversible electroporation. In some embodiments, the electrical pulsesmay be applied for a duration ranging from 1-1000 μs, or from 1-750 μs,or from 2-500 μs. In some embodiments, the electric pulses may have avoltage ranging from 0.1-2000 V, or from 100-1500 V, or from 500-1000 V.In another embodiment, the electric pulses may have a voltage rangingfrom 0.1-300 V, or from 50-100 V, or from 0.1- 50 V. In someembodiments, the electrical pulses may have a current amplitude rangingfrom 1-2000 mA, or from 100-1500 mA, or from 500-1000 mA.

A variety of waveforms can be used in electrical stimulation to targetspecific areas of the body. In some embodiments, a waveform of theelectrical pulse stimulation includes atleast one of biphasic,asymmetrical biphasic, polyphasic, and pulsed direct current (DC). Alsoin some embodiments, a current of the electrical pulse stimulationincludes at least one of sawtooth, trapezoid, triangular, rectangular,spike, or sine.

In some embodiments of the methods for treating damaged tissue, theplurality of sensors include at least one of Doppler probes, Hall Effectprobes, skin temperature probes, or a differential high voltage probe.In further embodiments of the methods, the recorded stimulation dataincludes at least one of current, waveform, voltage, and amplitude. Theelectrical stimulation pulses may be delivered in synchrony with theheart beat using sensor blood perfusion or electrical impedancemeasurements. The electrical pulses can be used to improve blood vesselcompliance during systole.

The indicators of wound healing include at least one of blood perfusion,pH, temperature, electrical activity, electrical impedance, a chemicalconcentration, a gas amount, wound size, or combination thereof. Otheraspects of the invention include methods for treating damaged tissuewherein the sensors measure the indicators of wound healing at variousintervals after treatment. In some embodiments, indicators of woundhealing may be measured post-treatment at 5 seconds, or 10 seconds, or30 seconds, or 1 min, or 5 min, or 10 min, or 30 min, or 1 hour, or 3hours, or 6 hours, or 12 hours, or 24 hours, or 36 hours, or 48 hours,or 72 hours, or 96 hours. In some embodiments, indicators of woundhealing may be measured in real-time for the first hour after treatmentends. In some embodiments of the methods, the future treatment protocolsare determined by the extent of a carry-over effect. The carry-overeffect may include an effect lasting beyond a treatment application.Post-treatment measurements of indicators of wound healing can be usedto determine the extent of a carry-over effect. Further embodiments ofthe methods include determining whether, after treatment, at least oneof the physiologic measurements has returned to a range of valuesassociated with a pre-treatment baseline, and initializing a subsequenttreatment based on the determination. Still further embodiments of themethods include determining whether, during treatment, one of thephysiologic measurements does not reach the range of values of at leastone of the physiologic measurements associated with previous treatments,and altering the energy delivery of a current treatment protocol and thefuture treatment protocol. The physiologic measurements may include oneor more indicators of wound healing. In some embodiments, if bloodperfusion drops below a pre-determined value, the device may betriggered through an automated feedback loop to start treatment.

In some embodiments of methods for treating damaged tissue, the energydelivery may be altered by changing the frequency, duration, oramplitude of the electrical pulse stimulation. In other embodiments, theenergy delivery may be altered by changing the frequency or duration ofthe heating component. Also in some embodiments, blood perfusion orelectrical impedance measurements may be compared to a predeterminedvalue, and the therapeutic delivery may be altered until themeasurements taken during the diseased state resemble the predeterminedvalue.

Other aspects of the invention include methods for determiningnormalization of blood flow using correlation and matched filtering.These methods provide a means to compute the similarity of bloodperfusion or electrical impedance measurements from a template normalstate to an unknown diseased state (e.g., absence of dicrotic notch inblood flow waveform for diabetic patients). This enables one todetermine the extent of blood flow normalization, which can be used tocontrol the time course of treatment. In some embodiments, the extent ofwound healing may be tracked based on feedback from sensor recordings.The user may be prompted to change the position of the electrodes basedon the electrical impedance or other sensor recordings. In otherembodiments, the user may be prompted to change treatment parametersassociated with heat and/or electrical stimulation delivery. Furtherembodiments include determining whether, after treatment, one of thephysiologic measurements has returned to a range of values associatedwith a pre-treatment baseline, and notifying the user. A subject may usean application to photograph the damaged tissue as treatment progresses.In some embodiments, photographs may be uploaded using an application.Uploaded photographs may be accessed by a clinician.

In some embodiments a patient computing device, housing a camera, may beused by the patient to take photographs. In another embodiment, thepatient computing device is configured to send and/or receive wirelesssignals. In an embodiment, the patient computing device is a mobiletelephone device, for example, a smartphone. In another embodiment, thepatient computing device is a home computer or laptop computer. Inanother embodiments, the patient computing device is a tablet. In someembodiments, the patient computing device is configured to be connectedto a camera by a physical connection, such as a wire or other connectionfor transmitting signals. In another embodiment, the patient computingdevice can send and/or receive wireless signals to and/or from thecamera.

In some embodiments, the at least one control unit includes a thermostatfor selecting an amount of energy to maintain the tissue temperature.The heating component preferably contains a means for controlling theheat generated by the heating components, such as a thermostat control.In some embodiments, the thermostat control can be set to discontinueheating upon the skin reaching a specified temperature. In someembodiments, the heating component generates an amount of energy, whichhas been predetermined to maintain the tissue temperature at 50° C. to35° C. In preferred embodiments, the temperature range will beconstantly maintained in order to lower impedance and increaseconductance of stimulation. Tissue impedance varies throughout the bodyand conductivity depends on the water content of tissue. High watercontent decreases impedance and improves conductance. Skin impedance isalso inversely proportional to the temperature of the skin. Heatincreases moisture content, which promotes conductivity. Temperatureaffects the impedance of the skin, with reduced impedance at increasingcutaneous temperatures.

Heating components can be run with a variable voltage supply. Thevoltage supply may be from 1-120 V, or from 1-60 V, or from 1-24 V. Insome embodiments electrical stimulation may be used for both electricfield generation and heating (low-voltage, long pulses may be used toobviate the need for a separate heating component).

In some embodiments, the control unit for electrical stimulation canmanipulate variables comprising at least one of waveform, pulseduration, pulse width, and intensity. In some embodiments, theelectrodes include a plurality of electrodes. A plurality of electrodesis any number greater than 1, optionally at least 2, or at least 3, orat least 4, or at least 5, or at least 6. In one embodiment, theelectrodes include two or more electrical conductors.

In some embodiments, the electrodes are placed on a skin surface in ageneral region of interest. The general region of interest may be acritical nerve and/or a blood vessel that supplies the damaged tissue.The human cutaneous circulation is controlled by sympathetic adrenergicvasoconstrictor nerves that coexist with sympathetic vasodilator nerves,a less well understood system that is activated during increased heat.Sympathetic vasoconstrictor and vasodilator nerves innervate all areasof nonglabrous skin, whereas areas of glabrous skin (palms, soles, lips)are innervated only by sympathetic vasoconstrictor nerves. In someembodiments, the critical nerve is a vasoconstrictor nerve. In furtherembodiments, the vasoconstrictor nerve is a sciatic nerve.

Physiologic measurements (e.g., blood flow) can be used in real-time toguide electrode placement, monitor wound healing, and serve as controlinputs to the device. These measurements could include temperature,bioimpedance, photoplethysmography, and Doppler flow via laser ormusculoskeletal ultrasound. In some embodiments, the device is capableof guiding electrode placement around the wound or distal nerve.Electrode placement must be specific over an area of high water contentfor optimal stimulation. In some embodiments, placement on a skinsurface in a general region of interest is preferred.

The general region of interest in some embodiments is a nerve. Theintracellular components of nerve and muscle have high water contents of70% to 75%. Tissue impedance varies throughout the body and conductivitydepends on the water content of tissue. High water content decreasesimpedance and improves conductance.

In general, the control of the circulation of the skin can be dividedinto two types: (1) the local response, which consists of vasodilationor vasoconstriction of vascular endothelial cells caused by metabolitesand local pressure, heat, or shear stress on the blood vessel wall, and(2) central or global control, which consists of neurogenic control ofvasolidation/vasoconstriction by the hypothalamus in response to skinsurface temperature receptors. In Type-1 and Type-2 diabetes,vasodilation is impaired through direct damage to endothelial cells. Insome embodiments, the blood vessel is a femoral artery 103.

In some embodiments, a test pulse is delivered to determine a baselineelectrical impedance of the tissue and ensure proper connectivity of theelectrodes. Impedance is the opposition to current flow to the body.Electrodes are placed and a test is run to determine if the electrodeplacement permits sufficient current delivery to the nerve or wound. Atthis point, a treatment session of electrical stimulation can be startedand may continue until blood flow ceases to increase for a thresholdamount of time. In some embodiments, the threshold amount of time isfrom 1-30 min, or from 1-15 min, or from 2-5 min. If blood flow ceasesto increase, alternate parameters (stimulation waveform, heat level,etc.) may be administered.

The electrical pulses may be applied in in an amount, which has beenpredetermined to cause vasodilation of blood vessels, wherein theelectrical pulses may be applied for a duration ranging from 1-5000 μs,or from 2-1,000 μs, or from 5-500 μs, or from 10-50 μs. In someembodiments, the electric pulses may have a voltage ranging from 0.1-500V, or from 5-250 V, or from 50-100 V. In another embodiment, theelectric pulses may have a voltage ranging from 0.1-200 V, or from50-200 V, or from 100-200 V. In some embodiments, the electrical pulsesmay have a current amplitude from 1-500 mA, or from 5-250 mA, or from50-100 mA.

In other embodiments of the methods, the electrical pulses may beapplied in an amount, which has been predetermined to cause nervestimulation by using comparatively longer pulses or pulses of greaterstrength. In some embodiments, the electrical pulses may be applied fora duration ranging from 1-10000 μs, or from 2-5000 μs, or from 50-1000μs, or from 100-500 μs. In some embodiments, the electric pulses mayhave a voltage ranging from 0.1-1500 V, or from 50-1000 V, or from200-500 V. In another embodiment, the electric pulses may have a voltageranging from 0.1-200 V, or from 50-200 V, or from 100-200 V. In someembodiments, the electrical pulses may have a current amplitude from1-1500 mA, or from 50-1000 mA, or from 200-500 mA.

In other embodiments, the electrical pulses may be applied in an amount,which has been predetermined to kill bacteria via non-thermalirreversible electroporation. Non-healing wounds place patients at anincreased risk for infections from common bacteria found on the skin andin the environment. In some embodiments, the electrical pulses may beapplied for a duration ranging from 1-1000 μs, or from 1-750 μs, or from2-500 μs. In some embodiments, the electric pulses may have a voltageranging from 0.1-2000 V, or from 100- 1500 V, or from 500-1000 V. Inanother embodiment, the electric pulses may have a voltage ranging from0.1-300 V, or from 50-300 V, or from 100-300 V. In some embodiments, theelectrical pulses may have a current amplitude from 1-2000 mA, or from100-1500 mA, or from 500-1000 mA.

Also, in some embodiments, the waveform of the electrical pulsestimulation includes at least one of monophasic, biphasic, asymmetricalbiphasic, polyphasic, or pulsed direct current (DC) or other waveformsor types and combinations of currents may be used. In some embodiments,the current of the electric pulse stimulation includes at least one ofsawtooth, trapezoid, triangular, rectangular, spike, or sine.

In some embodiments, the recorded stimulation data may includeamplitude, waveform, current, voltage, and amount of energy. FIG. 3illustrates a display of stimulation data. For example, such stimulationdata may include: blood flow (301), skin temperature (302), andstimulation waveform (303) or other parameters may be quantified.

Also, in some embodiments, electrical stimulation pulses may bedelivered in synchrony with the heart beat using sensor blood perfusionor electrical impedance measurements.

In some embodiments, the electrical stimulation pulses can improve bloodvessel compliance during systole. A photoplethysmography (PPG) signalfrom a normal patient has several characteristic features, including asystolic peak, dicrotic notch, and diastolic peak. Reduced blood vesselcompliance is often observed in diabetes, and congestive heart failurecan result in shortening of the time between the systolic and diastolicpeaks. Additionally, this reduction can effectively mask the dicroticnotch. In some embodiments, the methods, systems, and devices can beconfigured to increase blood vessel compliance during systole. This canbe performed by delivering electrical stimulus in synchrony with theheartbeat.

In some embodiments, a plurality of sensors include at least one ofDoppler probes, Hall Effect probes, skin temperature probes, and adifferential high voltage probe, or other sensors may be used.

For example, one method of monitoring blood flow is to use a Dopplerblood flow ultrasound monitor where a collar is wrapped around oradjacent to the junction of two vessel ends and a small sensor elementthat is a part of the collar is connected by fine wires to a benchtop orbedside monitor.

In some embodiments, a wide-band Hall Effect sensor is used to monitorcurrent. A Hall effect sensor is a transducer that varies its outputvoltage in response to a magnetic field. Hall effect sensors are usedfor proximity switching, positioning, speed detection, and currentsensing applications.

Skin temperature probes are capable of monitoring the temperature of theskin at treated sites. In some embodiments, the skin temperature probesare capable of continuous temperature monitoring.

Differential high voltage probes can record voltage in real-time.Differential high voltage probes can be used to measure the voltagedifference between two test points. The human skin has an impedance toan alternating current of low frequency, but this impedance decreases asfrequency of the alternating electric current increases. Three separatebranches of the sympathetic nervous system control skin blood flow:adrenergic vasoconstrictor nerves that reduce (constrict) skin bloodvessels, and cholinergic and nitrogenic nerves that cause vasodilationof blood vessels by releasing the neurotransmitters, acetylcholine,nitric oxide or Substance P. In some embodiments, electrical stimulationcan be directed at a specific nerve to enhance the production ofacetylcholine, Substance P or nitric oxide (NO). In other embodiments,the indicators of wound healing are blood perfusion, pH, temperature,electrical activity, electrical impedance, a chemical concentration, agas amount, wound size, or combinations thereof.

In some embodiments, the sensors measure the indicators of wound healingat various intervals after treatment. These measurements can be used toquantify the long lasting effects of treatment, including but notlimited to, carry-over effects. Simultaneously delivering heat andelectrical stimulation creates a synergistic effect on blood flowresulting in carry-over effects that persist after delivery of theenergy. In some embodiments, the carry-over effects are long-lastingphysiological changes. These physiologic changes may include, but arenot limited to, changes in blood perfusion, pH, temperature, electricalimpedance, a chemical concentration, a gas amount, or a wound size. Insome embodiments, the method may include the following steps:determining whether after treatment, one of the physiologic measurementshas returned to a range of values associated with a pre-treatmentbaseline and initializing a subsequent treatment. In some embodiments,sensors are used to detect physiologic measurements during treatment andafter treatment. In some embodiments, measurements may be collectedcontinuously and analyzed remotely in real- time. Physiologicmeasurements can be detected at least 5 min, or at least 10 min, or atleast 15 min, or at least 30 min, or at least 1 hour, or at least 2hours, or at least 5 hours, or at least 10 hours, or at least 24 hours,or at least 36 hours, or at least 48 hours, or at least 72 hoursfollowing treatment. In some embodiments, physiologic measurements maybe detected at multiple time points following treatment.

Over time, a change in the responsiveness of the sensory system toastimulus may occur. Thus, in some embodiments, the methods furtherinclude determining whether during treatment, one of the physiologicmeasurements does not reach the levels associated with previoustreatments. This may be due to stimulus adaptation. The method may theninclude the step of altering the energy delivery of the currenttreatment. For example, when a specific treatment protocol fails toproduce a similar physiologic response, the treatment protocol for thecurrent treatment session can be altered until a similar physiologicresponse can be produced. Additionally or alternatively, the treatmentprotocol for future treatment sessions can be altered to achieve aphysiologic response that reaches levels associated with current and/orprevious treatment sessions.

In some embodiments, the energy delivery is altered by changing thefrequency, duration, or amplitude of the electrical pulse stimulation.In some embodiments, stimulation parameters of higher frequency can beused.

There are several temperature regulatory systems the body uses tomaintain stable body temperatures (homeostasis). The skin uses a complexcontrol system to respond to local stimuli such as pressure and heat, todissipate or save heat, and to maintain blood pressure with changes inbody position. Sufficient intensity of and exposure to a stimulus isneeded for activation of the temperature regulating center in thehypothalamus within the brain. The hypothalamus acts as the “body'sthermostat” to maintain a normal range of human body temperature from36° C. to 38° C. When sensory information reaches the hypothalamus, theinformation is integrated and interpreted along with information on thetemperature of the blood circulating through the hypothalamus.

In some embodiments, the energy delivery is altered by changing thefrequency or duration of the heating component. Elevating the tissuetemperature can result in an increase in blood flow to the area, whichis attributable in part to the vasodilatory response in surface bloodvessels. The increase in blood flow; however, may remove heat from thearea, whereas blood that is relatively cooler flows into the area,preventing excessive heat accumulation. Thus in some instances,therapeutic heating levels may not be reached because the increasedblood flow may not allow for adequate heat build-up in the area. Heataccumulation is affected by the intensity and duration of the stimulus,as well as the rate of heat absorption by the tissue. In someembodiments, increased levels of heat must be provided to cause thehypothalamus to increase blood flow to the area.

In some embodiments, the blood perfusion or electrical impedancemeasurements are compared to a predetermined value, and the therapeuticdelivery is altered until the diseased state resembles the predeterminedvalue. In some embodiments, the predetermined value if that found innormal (i.e., non-wounded) tissue at the same site (i.e. place on limb).In some embodiments, cross-correlation is used to correlate bloodperfusion or electrical impedance measurements from a template normalstate to an unknown diseased state. The cross-correlation function ismaximized when two signals have similar phase and frequency content.

In some embodiments, methods further include tracking the extent ofwound healing based on feedback from sensor recordings. Examples ofactive feedback systems for monitoring blood flow include, but are notlimited to impedance spectroscopy, photoplethysmography (PPG), or laserof ultrasound Doppler.

In some embodiments, the methods include the steps of determining thefuture treatment parameters by the extent of carry-over. Treatment withheat, increases blood flow initially, but eventually levels off. Forexample, addition of electrical stimulation may create a carry-overeffect. Carry-over effects refer to long-lasting physiological changesfollowing energy delivery. To date, the mechanism of the carry-overeffects is unknown. The system and devices may utilize feedback fromsensors to exploit carry-over effects and optimize wound healing. Theoptimal treatment protocol should maintain an improved physiologicmeasurement (e.g., increased blood flow) with the minimum number oftreatments by coordinating energy delivery with the cessation ofcarry-over effects.

In some embodiments, the method may include prompting a subject tochange the position of the electrodes after determining whether one ofthe physiologic measurements has returned to a range of valuesassociated with a pre-treatment baseline, and notifying the user.

Also, in some embodiments, an application may be used to photograph andmonitor ulcer size, allowing treatments to be administered at home. Anapplication may be used to transmit information about wound healing tothe clinician via pictures. For example, to monitor wound healing andtrack compliance, patients may use the WoundMAP app for measuring ulcerdimensions with a cellular device. Patients may also take 10 secondvideo recordings of their wound, and the clips may be processed inMATLAB (Natick, Mass., USA) using a custom Eulerian Video Magnificationscript for visualizing changes in skin blood flow. Or other methods tovisually record the wound may be used.

Systems for the Treatment Of Damaged Tissue

Also disclosed herein are systems that employ the methods and devicesdescribed herein. The system may include various components. Forexample, the system may include a processing device, a non-transitorycomputer-readable medium communicatively coupled to the processingdevice, wherein the processing device is configured to performoperations comprising receiving a data set associated with patientindicators of wound healing and stimulation data. The processing devicemay also be configured to store the data set; generate treatmentparameters based on the stored data by determining a relationshipbetween initial treatment parameters and plurality of the indicators ofwound healing and the stimulation data. The processing device may alsobe configured to electronically convert the stored data into the nextparameters based on the relationship. The processing device may also beconfigured to generate an interface for display that includes dataassociated with the indicators of wound healing and the stimulationdata.

FIG. 5 illustrates an embodiment of a control unit of a system 501 asdisclosed herein. The system includes a power switch 508 coupled to amicrocontroller 506 and an AC-DC converter 510, which is a type ofexternal power supply that may supply power to a rechargeable battery507. The microcontroller 506 may be a computer on a single integratedcircuit and may include one or more CPUs, memory, and programmableinput/output peripherals. In some embodiments, an analog-to-digitalconverter (AID) 514 is used to read analog sensors that can produce ananalog sensor and convert the data to a digital signal that can berecognized by the microcontroller 506. The digital to analog converter(D/A) may allow the microcontroller 506 to output analog signals orvoltage levels.

The microcontroller may be interfaced (in electrical communication) withan LCD display 504 capable of displaying electrical stimulationwaveform. The output terminal of the amplifier 513 may be connected tothe electrodes 531. In this way, the amplifier and associated circuitrycan act as a voltage follower with unity gain and provide a high inputimpedance at the terminal.

The output terminal of the MOSFET Power Controller 502 may be connectedto the heat coil 530. A power MOSFET is a specific type of metal oxidesemiconductor field- effect transistor. MOSFETs are designed to handlesignificant power levels. In other embodiments, the power semiconductordevice may be an insulated-gate bipolar transistor (IGBT). The powerMOSFET 502 is a low-voltage (less than 200 V).

The Bluetooth module 511 is a wireless technology for exchanging dataover short distances from fixed and mobile devices. The Bluetooth modulemay be configured to exchange data with the external blood flowmonitoring module 532. The data collected from the external blood flowmonitoring module 532 can be displayed on the LCD display 512.

Computer Systems and Computer Readable Media

In certain embodiments, the invention may include a system. The systemmay include at least some of the devices of the invention. Also, thesystem may include at least some of the components for performing themethod. In other embodiments, the invention includes software for usewith the methods or systems.

The system, as described in the present technique or any of itscomponents, may be embodied in the form of a computer system. Typicalexamples of a computer system include a general-purpose computer, aprogrammed microprocessor, a microcontroller, a peripheral integratedcircuit element, and other devices or arrangements of devices that arecapable of implementing the steps that constitute the method of thepresent technique.

A computer system may include a computer, an input device, a displayunit, and/or the Internet. The computer may further include amicroprocessor. The microprocessor may be connected to a communicationbus. The computer may also include a memory. The memory may includerandom access memory (RAM) and read only memory (ROM). The computersystem may further include a storage device. The storage device can be ahard disk drive or a removable storage drive such as a floppy diskdrive, optical disk drive, etc. The storage device can also be othersimilar means for loading computer programs or other instructions intothe computer system. The computer system may also include acommunication unit. The communication unit allows the computer toconnect to other databases and the Internet through an 1/0 interface.The communication unit allows the transfer to, as well as reception ofdata from, other databases. The communication unit may include a modem,an Ethernet card, or any similar device, which enables the computersystem to connect to databases and networks such as LAN, MAN, WAN andthe Internet. The computer system thus may facilitate inputs from a userthrough input device, accessible to the system through 1/0 interface.

A computing device typically will include an operating system thatprovides executable program instructions for the general administrationand operation of that computing device, and typically will include acomputer-readable storage medium (e.g., a hard disk, random accessmemory, read only memory, etc.) storing instructions that, when executedby a processor of the server, allow the computing device to perform itsintended functions. Suitable implementations for the operating systemand general functionality of the computing device are known orcommercially available, and are readily implemented by persons havingordinary skill in the art, particularly in light of the disclosureherein.

The computer system executes a set of instructions that are stored inone or more storage elements, in order to process input data. Thestorage elements may also hold data or other information as desired. Thestorage element may be in the form of an information source or aphysical memory element present in the processing machine.

The environment can include a variety of data stores and other memoryand storage media as discussed above. These can reside in a variety oflocations, such as on a storage medium local to (and/or resident in) oneor more of the computers or remote from any or all of the computersacross the network. In a particular set of embodiments, the informationmay reside in a storage-area network (“SAN”) familiar to those skilledin the art. Similarly, any necessary files for performing the functionsattributed to the computers, servers, or other network devices may bestored locally and/or remotely, as appropriate. Where a system includescomputing devices, each such device can include hardware elements thatmay be electrically coupled via a bus, the elements including, forexample, at least one central processing unit (CPU), at least one inputdevice (e.g., a mouse, keyboard, controller, touch screen, or keypad),and at least one output device (e.g., a display device, printer, orspeaker). Such a system may also include one or more storage devices,such as disk drives, optical storage devices, and solid-state storagedevices such as random access memory (“RAM”) or read-only memory(“ROM”), as well as removable media devices, memory cards, flash cards,etc.

Such devices also can include a computer-readable storage media reader,a communications device (e.g., a modem, a network card (wireless orwired), an infrared communication device, etc.), and working memory asdescribed above. The computer-readable storage media reader can beconnected with, or configured to receive, a computer-readable storagemedium, representing remote, local, fixed, and/or removable storagedevices as well as storage media for temporarily and/or more permanentlycontaining, storing, transmitting, and retrieving computer-readableinformation. The system and various devices also typically will includea number of software applications, modules, services, or other elementslocated within at least one working memory device, including anoperating system and application programs, such as a client applicationor Web browser. It should be appreciated that alternate embodiments mayhave numerous variations from that described above. For example,customized hardware might also be used and/or particular elements mightbe implemented in hardware, software (including portable software, suchas applets), or both. Further, connection to other computing devicessuch as network input/output devices may be employed.

Non-transient storage media and computer readable media for containingcode, or portions of code, can include any appropriate media known orused in the art, including storage media and communication media, suchas but not limited to volatile and non-volatile, removable andnon-removable media implemented in any method or technology for storageand/or transmission of information such as computer readableinstructions, data structures, program modules, or other data, includingRAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM,digital versatile disk (DVD) or other optical storage, magneticcassettes, magnetic tape, magnetic disk storage or other magneticstorage devices, or any other medium which can be used to store thedesired information and which can be accessed by the a system device.Based on the disclosure and teachings provided herein, a person ofordinary skill in the art will appreciate other ways and/or methods toimplement the various embodiments.

A computer-readable medium may include, but is not limited to, anelectronic, optical, magnetic, or other storage device capable ofproviding a processor with computer- readable instructions. Otherexamples include, but are not limited to, a floppy disk, CD-ROM, DVD,magnetic disk, memory chip, ROM, RAM, SRAM, DRAM, content- addressablememory (“CAM”), DDR, flash memory such as NAND flash or NOR flash, anASIC, a configured processor, optical storage, magnetic tape or othermagnetic storage, or any other medium from which a computer processorcan read instructions. In one embodiment, the computing device mayinclude a single type of computer-readable medium such as random accessmemory (RAM). In other embodiments, the computing device may include twoor more types of computer-readable medium such as random access memory(RAM), a disk drive, and cache. The computing device may be incommunication with one or more external computer-readable mediums suchas an external hard disk drive or an external DVD or Blu-Ray drive.

As discussed above, the embodiment includes a processor, which isconfigured to execute computer-executable program instructions and/or toaccess information stored in memory. The instructions may includeprocessor-specific instructions generated by a compiler and/or aninterpreter from code written in any suitable computer-programminglanguage including, for example, C, C++, C#, Visual Basic, Java, Python,Perl, JavaScript, and ActionScript (Adobe Systems, Mountain View,Calif.). In an embodiment, the computing device includes a singleprocessor. In other embodiments, the device includes two or moreprocessors. Such processors may include a microprocessor, a digitalsignal processor (DSP), an application-specific integrated circuit(ASIC), field programmable gate arrays (FPGAs), and state machines. Suchprocessors may further include programmable electronic devices such asPLCs, programmable interrupt controllers (PICs), programmable logicdevices (PLDs), programmable read-only memories (PROMs), electronicallyprogrammable read-only memories (EPROMs or EEPROMs), or other similardevices.

The computing device includes a network interface. In some embodiments,the network interface is configured for communicating via wired orwireless communication links. For example, the network interface mayallow for communication over networks via Ethernet, IEEE 802.11 (Wi-Fi),802.16 (Wi-Max), Bluetooth, infrared, etc. As another example, networkinterface may allow for communication over networks such as CDMA, GSM,UMTS, or other cellular communication networks. In some embodiments, thenetwork interface may allow for point-to-point connections with anotherdevice, such as via the Universal Serial Bus (USB), 1394 FireWire,serial or parallel connections, or similar interfaces. Some embodimentsof suitable computing devices may include two or more network interfacesfor communication over one or more networks. In some embodiments, thecomputing device may include a data store in addition to or in place ofa network interface.

Some embodiments of suitable computing devices may include or be incommunication with a number of external or internal devices such as amouse, a CD-ROM, DVD, a keyboard, a display, audio speakers, one or moremicrophones, or any other input or output devices. For example, thecomputing device may be in communication with various user interfacedevices and a display. The display may use any suitable technologyincluding, but not limited to, LCD, LED, CRT, and the like.

The set of instructions for execution by the computer system may includevarious commands that instruct the processing machine to performspecific tasks such as the steps that constitute the method of thepresent technique. The set of instructions may be in the form of asoftware program. Further, the software may be in the form of acollection of separate programs, a program module with a larger programor a portion of a program module, as in the present technique. Thesoftware may also include modular programming in the form ofobject-oriented programming. The processing of input data by theprocessing machine may be in response to user commands, results ofprevious processing, or a request made by another processing machine.

While the present invention has been disclosed with references tocertain embodiments, numerous modifications, alterations and changes tothe described embodiments are possible without departing from the scopeand spirit of the present invention, as defined in the appended claims.Accordingly, it is intended that the present invention not be limited tothe described embodiments, but that it have the full scope defined bythe language of the following claims, and equivalents thereof.

EXAMPLES

The following examples describe methods of treatment with a shortenedhealing time and are to illustrate but not limit the invention.

Example 1. Prototypic Therapeutic Device and Methods

A prototype device was built as a stand-alone, at-home system fordelivering heat and electrical stimulation to DFUs. An internal heatingcoil was encapsulated by several fabric layers to ensure uniform heatingof the lower-limb (FIG. 2). Electrical stimulation was delivered usingan external FDA approved device (EMPI continuum (continuum electricalstimulation device), St. Paul, Minn., USA), because it is capable ofdelivering a variety of pulse parameters. Under an approved IRB, fourhealthy subjects were tested. The heating component was set so that theskin temperature reached 37° C., and a symmetric, biphasic waveform wasapplied with currents reaching 20 mA. Data was acquired using a Biopacsystem (MP150, Goleta, Calif., USA) outfitted with a laser Doppler flowmeter and skin temperature probe (FIG. 7). Additionally, a high voltageprobe was used to record the output of the stimulator in real-time. Asnapshot of the data (FIG. 3) shows traces for blood flow measured inblood perfusion units, skin temperature, and stimulator output voltage.By averaging over the course of the entire treatment, the resultsindicate that blood flow more than doubles while wearing the device(FIG. 4).

Example 2. Determining the Effects of Heat Alone on Healing of DFUs

The therapeutic device will be compared to a heating pad (2014-915Xpressheat Heating Pad, Sunbeam, Boca Raton, Fla., USA) applied at thebottom of the foot with only vasoconstrictor nerves (typical location ofDFU). Ten healthy subjects and ten subjects with Type-2 diabetes and nowound will be recruited. On different days and at random, subjects willbe instructed to either wear the therapeutic device or foot sole heatingpad. The subjects will lie supine on an examination table. Blood flowwill be monitored continuously in the soles of both feet using the MP150data acquisition system (Biopac Systems, Inc., Goleta, Calif., USA)combined with two laser Doppler flow amplifiers (LDF100C) and twosurface probes (TSD140) from Biopac Systems. Temperature will bemonitored continuously at the skin surface in the soles of both feetusing the MP150 combined with two skin temperature amplifiers (SKTI00C)and two surface probes (TSD202) from Biopac Systems. Each session willlast 1 hour. The subjects will undergo 15 minutes of baseline recordingsfollowed by 45 minutes of heating (three, 15 min increments ofincreasing temperature (32, 35, and 38° C.)). In this study, noelectrical stimulation will be applied, so as to isolate the effects ofheat alone applied in various configurations.

Example 3. Treatment of DFUs with the Therapeutic Device

The electrical stimulation waveform and electrode location will betested with the therapeutic device, and the temperature will be set tomaximize blood flow to the treated leg. Three groups of ten subjectswith Type-2 diabetes will be recruited to test three different waveforms(biphasic, asymmetrical biphasic, pulsed DC) synthesized by the EMPIcontinuum stimulator. To record voltage in real-time during treatment,the stimulator output will be split between adhesive electrodes on thesubject's foot and a differential high-voltage probe (DP-25, PintekElectronics, New Taipei City, Taiwan) connected to the analog input ofthe MP150 acquisition system. Additionally, the current will bemonitored using a wide-band Hall Effect sensor (2877, PearsonElectronics, Palo Alto, Calif., USA) connected to a secondary analoginput. The pulse width will be fixed at 300 ps and the amplitude will beincreased to the highest level at which the subject is comfortable. Thesubjects will undergo 15 minutes of baseline recordings followed by 15minutes of stimulation with the electrodes located on the foot sole and15 minutes with the electrodes located across the sciatic nerve.

Example 4. Treatment of Non-Healing Wounds with Therapeutic Device

Ten patients with Type-2 diabetes and a neuropathic wound to test themat-home will be recruited. Only patients with no wound healing for twomonths prior will be selected and serve as their own control. Prior tostarting treatment, patients will receive an examination of the woundand training on how to use the therapeutic device with electricalstimulation. The heating parameters will be chosen based on thecombination of parameters from Example 3 that maximize blood flow to thefoot. Baseline measurements of blood flow, blood pressure, heart rate,and wound dimensions will be taken. Patients will be divided into twogroups for therapeutic treatment on three or six days per week. Tomonitor wound healing and track compliance, patients will use theWoundMAP app for measuring ulcer dimensions with a cell phone. They willalso take 10 second video recordings of their wound, and the clips willbe processed in MATLAB (Natick, Mass., USA) using a custom EulerianVideo Magnification script for visualizing changes in skin blood flow.At the end of the four week period, patients will return to the clinicfor repeat baseline measurements.

Accordingly, the device and methods described herein for the treatmentof DFUs or other non-healing ulcers, can improve blood flow locally tothe wound through various means of electrical stimulation andapplication of heat. A portable device, for at-home use, allows forincreased treatment times/frequency, lowers costs, and greaterefficiency.

The following number paragraphs list various combinations of features orsteps described herein that may be used in the treatment of damagetissue:

A therapeutic device for treating damaged tissue comprising:

a heating component; wherein heat can be applied to a limb;a plurality of electrodes, wherein at least one electrode supplieselectrical pulse stimulation;a plurality of sensors, wherein at least one sensor is configured tomeasure at least one indicator of wound healing;a pulse generator electrically coupled with the plurality of electrodes,wherein the pulse generator is configured to generate a plurality ofelectrical impulses for delivering the electrical pulse stimulationtreatment to a subject through at least one of the electrodes;at least one control unit to operate the electrical pulse stimulationand the heating component; and a processor, wherein the processorcomprises processing logic and telemetry to determine the optimaltreatment regimen for maximizing blood flow based on carry-over effects.

The device of paragraph 1, wherein the heating component is a flexibleinternal heating coil.

The device of paragraph 1 wherein the device comprises a plurality oflayers comprising:

a heating component layer having a first side and second side;an inner layer comprising a plurality of dissimilar materials, whereinthe inner layer contacts the subject's skin;an outer layer comprising a plurality of dissimilar materials; anda discontinuous adhesive layer, which affixes the first side of theheating layer to the inner layer and the second side of the heatingcomponent layer to the outer layer.

The device of paragraph 3, wherein the inner layer comprises two or moresublayers.

The device of paragraph 4, wherein a first sublayer is an innerinsulative sublayer, wherein the inner insulative sublayer is anabsorbent polymer, and wherein the inner insulative sublayer contactsthe subject's skin.

The device of paragraph 5, wherein the inner insulative sublayercomprises at least one of fleece, wool, cotton, nylon, polyester, or acombination thereof.

The device of paragraph 4, wherein a second sublayer is an innerconductive sublayer, wherein the inner conductive sublayer is an organicpolymer.

The device of paragraph 7, wherein the organic polymer comprises atleast one of polyethylene terephthalate (PET), metallized polyethyleneterephthalate (MPET), or biaxially oriented PET(BoPET).

The device of paragraph 5, wherein the first sublayer is coated with ananti-microbial material.

The device of paragraph 3, wherein the inner layer uniformly distributesheat over the whole limb.

The device of paragraph 3, wherein the thickness of the inner layer isfrom 1-50 mm or from 5-10 mm.

The device of paragraph 3 wherein the thickness of the heating componentlayer is from 1-20 mm or from 1-5 mm.

The device of paragraph 3, wherein the outer layer comprises two or moresublayers.

The device of paragraph 13, wherein a first outer sublayer is a plasticmesh layer, wherein, the plastic mesh layer contacts the second side ofthe heating component layer.

The device of paragraph 13, wherein a second outer sublayer is asynthetic rubber.

The device of paragraph 15, wherein the synthetic rubber comprises atleast one of neoprene, polyurethane, or nitrile rubber.

The device of paragraph 3 wherein the thickness of the outer layer isfrom 1-50 mm, or from 2-25 mm, or from 5-10 mm.

The device of paragraph 1, wherein the plurality of sensors comprise atleast one of Doppler probes, Hall Effect probes, skin temperatureprobes, or a differential high voltage probe.

The device of paragraph 1, wherein the at least one control unitcomprises a thermostat for selecting an amount of energy to maintain thetissue temperature.

A method of treating damaged tissue comprising the steps of: identifyingtissue to be treated;

placing around a limb, a therapeutic device comprising:a heating component, wherein heat can be applied to the limb; aplurality of electrodes, wherein at least one electrode supplieselectrical pulse stimulation;a plurality of sensors, wherein at least one sensor is configured tomeasure indicators of wound healing;a pulse generator electrically coupled with the plurality of electrodes,wherein the pulse generator is configured to generate a plurality ofelectrical impulses for delivering the electrical pulse stimulationtreatment to a subject through at least one of the electrodes;at least one control unit to operate the electrical pulse stimulation orthe heating component; and a processor, wherein the processor comprisesprocessing logic and telemetry to determine the optimal treatmentregimen for maximizing blood flow based on carry-over effects;selecting a treatment protocol; applying heat to a limb;simultaneously generating an electrical impulse through the plurality ofelectrodes;using a plurality of sensors to record stimulation data and indicatorsof wound healing during treatment and after treatment, wherein theindicators are physiologic and bioimpedance measurements; andenabling, disabling, altering the electrical impulse stimulation andheat based on the recorded stimulation data and the recorded indicators.

The method of paragraph 20, wherein the device is placed around a limb.

The method of paragraph 20, wherein the limb is a leg.

The method of paragraph 20, wherein the device is placed around a leg orone or more sections thereof.

The method of paragraph 20, wherein the at least one control unitcomprises a thermostat for selecting an amount of energy to maintain thetissue temperature.

The method of paragraph 20, wherein the heating component generates anamount of energy which has been predetermined to maintain the tissuetemperature from 45° C.-30° C. or from 40-35° C.

The method of paragraph 20, wherein the electrodes comprise two or moreelectrical conductors.

The method of paragraph 20, wherein the electrodes are placed on a skinsurface in a general region of interest.

The method of paragraph 27, wherein the general region of interest is acritical nerve or blood vessel.

The method of paragraph 20, wherein the critical nerve is avasoconstrictor nerve.

The method of paragraph 20, wherein the vasoconstrictor nerve is asciatic nerve.

The method of paragraph 20, wherein the blood vessel is a femoralartery.

The method of paragraph 20, wherein a test pulse is delivered todetermine the baseline electrical impedance of the tissue and ensureproper connectivity of the electrodes.

The method of paragraph 20, wherein the electrical pulses are applied inan amount which has been predetermined to cause vasodilation of bloodvessels, wherein the electrical pulses are applied for a durationranging from 10-50 μs, having a voltage ranging from 50-100 V, and witha current amplitude from 50-100 mA.

The method of paragraph 20, wherein the electrical pulses are applied inan amount which has been predetermined to cause nerve stimulation,wherein the electrical pulses are applied for a duration ranging from50-500 μs, having a voltage in a range of 200-500 V, and with a currentamplitude from 200-500 mA.

The method of paragraph 20, wherein the electrical pulses are applied inan amount which has been predetermined to kill bacteria via non-thermalirreversible electroporation, wherein the electrical pulses are appliedfor a duration ranging from 2-500 μs, and the pulses produce a variableAC voltage having a voltage ranging from 500-1000 V, and with a currentamplitude from 500-1000 mA.

The method of paragraph 20, wherein a waveform of the electrical pulsestimulation comprises at least one of biphasic, asymmetrical biphasic,polyphasic, and pulsed direct current (DC).

The method of paragraph 20, wherein a current of the electrical pulsestimulation comprises at least one of sawtooth, trapezoid, triangular,rectangular, spike, or sme.

The method of paragraph 20, wherein the plurality of sensors comprise atleast one of Doppler probes, Hall Effect probes, skin temperatureprobes, or a differential high voltage probe.

The method of paragraph 20, wherein the recorded stimulation datacomprises at least one of current, waveform, voltage, and amplitude.

The method of paragraph 20, wherein the electrical stimulation pulsesare delivered in synchrony with the heart beat using sensor bloodperfusion or electrical impedance measurements.

The method of paragraph 20, wherein the electrical pulses improve bloodvessel compliance during systole.

The method of paragraph 20, wherein the indicators of wound healing areblood perfusion, pH, temperature, electrical activity, electricalimpedance, a chemical concentration, a gas amount, wound size, orcombination thereof.

The method of paragraph 20, wherein the sensors measure the indicatorsof wound healing every six hours post-treatment.

The method of paragraph 20, wherein the future treatment protocols aredetermined by the extent of a carry-over effect.

The method of paragraph 43, wherein the carry-over effect is an effectlasting beyond a treatment application.

The method of paragraph 20, further comprising determining whether,after treatment, one of the physiologic measurements has returned to arange of values associated with a pre-treatment baseline, andinitializing a subsequent treatment based on the determination.

The method of paragraph 20, further comprising determining whether,during treatment, one of the physiologic measurements does not reach thelevels associated with previous treatments, and altering the energydelivery of a current treatment protocol and the future treatmentprotocol.

The method of paragraph 20, wherein the energy delivery is altered bychanging the frequency, duration, or amplitude of the electrical pulsestimulation.

The method of paragraph 20, wherein the energy delivery is altered bychanging the frequency or duration of the heating component.

The method of paragraph 20, wherein blood perfusion or electricalimpedance measurements are compared to a predetermined value, and thetherapeutic delivery is altered until the diseased state resembles thepredetermined value.

The method of paragraph 20, wherein cross-correlation is used tocorrelate blood perfusion or electrical impedance measurements from atemplate normal state to an unknown diseased state. Thecross-correlation function is maximized when two signals have similarphase and frequency content.

The method of paragraph 20, further comprising tracking the extent ofwound healing based on feedback from sensor recordings.

The method of paragraph 20, wherein the user is prompted to change theposition of the electrodes based on the electrical impedance or othersensor recordings.

The method of paragraph 20, further comprising determining whether,after treatment, one of the physiologic measurements has returned to arange of values associated with a pre-treatment baseline, and notifyingthe user.

The method of paragraph 20, wherein a subject uses an application tophotograph the damaged tissue as treatment progresses.

The method of paragraph 20, wherein photographs are uploaded using theapplication.

A system comprising:a processing device;a non-transitory computer-readable medium communicatively coupled to theprocessing device, wherein the processing device is configured toperform operations comprising:receiving a data set associated with patient indicators of wound healingand stimulation data storing the data set;generating treatment parameters based on the stored data by determininga relationship between initial treatment parameters and plurality of theindicators of wound healing and the stimulation data;electronically converting the stored data into the next parameters basedon the relationship; and generating an interface for display thatincludes data associated with the indicators of wound healing and thestimulation data.

We claim:
 1. A therapeutic device for an area of the patient, the areaincluding skin and an ulcer, and said therapeutic device comprising: acovering configured to cover the area of the patient including theulcer, said covering including a heating component adapted to cover theulcer, and said heating component including a heat source that generatesheat to apply and transfer the heat to the area through the skin and tothe ulcer; a sensor to detect blood perfusion in the area of the ulcer;and a control unit in communication with said sensor and configured tocontrol the heating component and to adjust the heat based on input fromsaid sensor.
 2. The therapeutic device of claim 1, wherein said sensorcomprises a first sensor, further comprising a second sensor, saidsecond sensor configured to detect, read and/or measure at least oneother physiological characteristic of the patient that is indicative ofwound healing, the at least one other physiological characteristic ofthe patient being selected from the group consisting of moisture, pH,and bioimpedance, and said control unit in communication with said firstand second sensors to monitor wound healing based on input from saidfirst and second sensors.
 3. The therapeutic device of claim 2, whereinsaid second sensor is configured to measure bioimpedance of the skin ofthe patient.
 4. The therapeutic device of claim 2, wherein said secondsensor is configured to measure the pH of the skin of the patient todetect an indication of infection and thereby measure at least oneindicator of wound healing.
 5. The therapeutic device of claim 1,wherein the area is on a limb of the patient, and said heating componentis adapted to cover the area and beyond the area and to cover at least40% of the limb to globally warm the limb and the area of the ulcer toraise the temperature of the limb and not just provide local warming ofthe skin and the ulcer.
 6. The therapeutic device of claim 1, whereinsaid heating component has a footprint, said covering including athermally conductive layer configured to transfer heat from said heatsource to a greater area than a footprint of said heating component toincrease the heat transfer efficiency of said heating component.
 7. Thetherapeutic device of claim 1, further comprising a plurality ofelectrodes adapted to apply electrical pulse stimulation to the area butspaced from the ulcer, and an electrical pulse generator adapted to bein electrical communication with an electrical supply and electricallycoupled with said plurality of electrodes, said electrical pulsegenerator being configured to generate a plurality of electricalimpulses at least one of said electrodes when coupled with theelectrical supply for delivering electrical pulse stimulation to thepatient through said at least one of said electrodes wherein saidelectrical pulse generator is configured to apply a biphasic wave formin a range of 0.25 mA to 100 mA with a pulse width in a range of 50 to500 microseconds.
 8. The therapeutic device of claim 7, wherein saidcontrol unit is configured to control said pulse generator to adjust theelectrical impulses based on input from said sensor.
 9. A therapeuticdevice for an area of the patient, the area including skin and an ulcer,and said therapeutic device comprising: a heating component adapted tocover the ulcer and including a heat source that generates heat to applyand transfer the heat to the area through the skin and to the ulcer; aplurality of electrodes adapted to apply to the patient spaced from thearea of ulcer; a sensor to detect blood perfusion in the area of theulcer; an electrical pulse generator adapted to be in electricalcommunication with an electrical supply and electrically coupled withsaid plurality of electrodes, said electrical pulse generator beingconfigured to generate a plurality of electrical impulses at least oneof said electrodes when coupled with said electrical supply fordelivering electrical pulse stimulation to the patient through said atleast one of said electrodes wherein said electrical pulse generator isconfigured to apply a biphasic wave form in a range of 0.25 mA to 100 mAwith a pulse width in a range of 50 to 500 microseconds; a control unitconfigured to control said pulse generator and said heating componentwherein said control unit is configured to applying the heat andelectrical stimulation at the same time.
 10. The therapeutic deviceaccording to claim 9, wherein said control unit is configured to controlsaid heating component and/or said electrical pulse generator based oninput from said sensor.
 11. The device of claim 10, wherein said controlunit includes a communication device for transmitting information fromsaid sensor to a remote device.
 12. The device of claim 10, wherein saidcontrol unit includes a communication device for transmitting a signalfrom or a state of said first or second sensor to a remote device.
 13. Atherapeutic device for an area of the patient, the area including skinand an ulcer, and said therapeutic device comprising: a plurality ofelectrodes adapted to apply electrical pulse stimulation to the area butspaced from the ulcer; an electrical pulse generator adapted to be inelectrical communication with an electrical supply and electricallycoupled with said plurality of electrodes, said electrical pulsegenerator being configured to generate a plurality of electricalimpulses at least one of said electrodes when coupled with theelectrical supply for delivering electrical pulse stimulation to thepatient through said at least one of said electrodes wherein saidelectrical pulse generator is configured to apply a biphasic wave formin a range of 0.25 mA to 100 mA with a pulse width in a range of 50 to500 microseconds; and a control unit in communication with andconfigured to control said pulse generator to adjust the electricalimpulses.
 14. The therapeutic device of claim 13, further comprising asensor to detect blood perfusion in the area.
 15. The therapeutic deviceof claim 14, wherein said control unit adjusts said electrical pulsestimulation based on said sensor.
 16. The therapeutic device of claim14, wherein said sensor comprises a first sensor, further comprising asecond sensor, said second sensor configured to detect, read and/ormeasure at least one other physiological characteristic of the patientthat is indicative of wound healing, said at least one otherphysiological characteristic of the patient being selected from thegroup consisting of moisture, pH, and bioimpedance, and said controlunit in communication with said first and second sensors to monitorwound healing based on input or states of said first and second sensors.17. The therapeutic device of claim 16, wherein said second sensor isconfigured to measure bioimpedance of the skin.
 18. The therapeuticdevice of claim 16, wherein said second sensor is configured to measurethe pH of the skin of the patient to detect an indication of infectionand thereby measure at least one indicator of wound healing.
 19. Thetherapeutic device of claim 13, further comprising a covering configuredto cover the area of the patient including the ulcer and a heatingcomponent at said covering, said heating component including a heatsource that generates heat to apply and transfer the heat through theskin and to the ulcer.
 20. The therapeutic device of claim 19, whereinthe area is on a limb of the patient, and said heating component isadapted to cover the area and beyond the area and to cover at least 40%of the limb to globally warm the limb and the area of the ulcer to raisethe temperature of the limb and not just provide local warming of theskin and the ulcer.